Cell signaling and transcription factors in pancreatic islet development and function

胰岛发育和功能中的细胞信号传导和转录因子

• 批准号: 10783216
• 负责人: David Lorberbaum
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-06 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10783216
• 关键词: Address; Adult; Advisory Committees; Affect; Beta Cell; Blood Glucose; Cause of Death; Cell Differentiation process; Cell physiology; Cells; Cessation of life; DNA; Data; Defect; Development; Diabetes Mellitus; Disease; Embryo; Endocrine; Engineering; Enzymes; Epitopes; Excision; Follow-Up Studies; Functional disorder; GATA6 transcription factor; Genes; Genetic Transcription; Human; In Vitro; Individual; Insulin; Islet Cell; Islets of Langerhans; Knowledge; Literature; Maintenance; Mediating; Mediator; Minor; Modeling; Molecular; Mus; Pancreas; Pathway interactions; Patients; Persons; Phenotype; Physiological; Pilot Projects; Play; Population; Process; Protocols documentation; Regulatory Pathway; Replacement Therapy; Reporting; Repression; Research; Role; Signal Transduction; Specific qualifier value; Structure of beta Cell of islet; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Tretinoin; United States; WNT Signaling Pathway; Work; beta cell replacement; blood glucose regulation; cell replacement therapy; cofactor; cost; cost estimate; diabetes management; differentiation protocol; endocrine pancreas development; genetic analysis; human pluripotent stem cell; improved; in vivo; in vivo Model; innovation; islet; mouse model; novel; pancreas development; pancreatic islet function; prevent; progenitor; synergism; tool; transcription factor; type I and type II diabetes

PROJECT SUMMARY AND ABSTRACT Over the past several decades the number of people in the United States with diabetes has steadily increased and reports from 2020 indicate nearly 10.5% of the population have the disease, leading to more than 270,000 deaths and an estimated cost of $327 billion. While tremendous effort is directed towards managing diabetes, there is no cure. One promising treatment is islet replacement therapy, addressing a major underlying issue in both type 1 and type 2 diabetes: dysfunctional and dying β cells. This treatment, however, is not widely accessible because of a lack of donor material. To overcome this limitation, insulin producing β cells can be generated from human pluripotent stem cells (hPSCs) in vitro, but despite great strides even the best protocols are unable to efficiently produce mature β cell populations for transplant. To improve this therapeutic strategy, it is essential to clarify mechanisms of pancreas development using in vivo models that will allow us to refine β cell differentiation protocols. Nearly all of the information used to formulate these protocols is derived from developmental studies in mice, which have provided a roadmap specifying the sequential addition or removal or signaling factors to promote β cell formation. For example, retinoic acid (RA) is included in early stages of all β cell differentiation protocols to specify pancreatic progenitors simulating numerous studies conducted in mice. Despite its importance at the onset of pancreas development, little is known about RA later in mouse or human pancreagenesis. To address this knowledge gap, we performed studies that identified a novel role for RA during endocrine progenitor specification where RA represses WNT signaling to promote β cell differentiation. Since RA clearly does not act alone in this process, I also began to examine the role of GATA factors during pancreas development as well, since previous work has demonstrated RA-GATA synergy in several models, including human β cell differentiations. Furthermore, haploinsufficiency of GATA6 in humans leads to pancreas agenesis in more than 50% of cases, yet this same deletion in mice and human β cell differentiations results in minor phenotypes, suggesting that background modifiers, like RA signaling, could be playing a major role. My preliminary studies described in this proposal demonstrate significant synergy between RA and GATA TFs in mice: simultaneous inhibition leads to drastically fewer and dysfunctional endocrine cells that contributes to severe physiological defects during development and adulthood. With guidance from these preliminary data, I will clarify the regulatory mechanisms defining endocrine specification, β cell development, and islet function by testing the hypothesis that synergy between RA signaling and GATA transcription factors is essential for embryonic pancreas development and adult islet function.

项目摘要和摘要 在过去的几十年中，美国患有糖尿病的人数悄然增加 2020年的报告表明，几乎10.5％的人口患有这种疾病，导致超过270,000 死亡人数和估计成本为3270亿美元。虽然巨大的努力是针对糖尿病的，但 无法治愈。一种承诺治疗是胰岛替代疗法，解决了 1型和2型糖尿病：功能失调和垂死的β细胞。但是，这种治疗并不广泛 由于缺乏供体材料，因此可以访问。为了克服这一限制，产生β细胞的胰岛素可以是 在体外由人多能干细胞（HPSC）产生 无法有效产生成熟的β细胞群进行移植。为了改善这种治疗策略， 必须使用体内模型来阐明胰腺发育机制，这使我们能够完善β 细胞分化方案。几乎所有用于制定这些协议的信息都是从 在小鼠中提供了指定顺序添加或去除的路线图的小鼠的发展研究 或信号传导因子促进β细胞形成。例如，视黄酸（RA）包括在所有的早期阶段 β细胞分化方案指定胰腺祖细胞模拟了许多研究 老鼠。尽管在胰腺发育开始时具有重要的意义，但对鼠标或 人类胰腺癌。为了解决这个知识差距，我们进行了研究，确定了新的作用 内分泌祖细胞规范期间RA，其中RA再现Wnt信号传导以促进β细胞 分化。由于RA在此过程中显然不是一个人行动，因此我也开始研究GATA的作用 胰腺发育过程中的因素也是以前的工作，因为先前的工作已经证明了Ra-gata协同作用 几种模型，包括人β细胞分化。此外，人类GATA6的单倍不足 在超过50％的病例中导致胰腺产生，但在小鼠和人β细胞中相同的缺失 区分导致次要表型，表明背景修饰符（如RA信号传导）可能是 扮演主要角色。我的初步研究中描述了明显的协同作用 在小鼠中RA和GATA TF之间：简单的抑制作用导致较少和功能失调 在发育和成年期间导致严重身体缺陷的内分泌细胞。和 这些初步数据的指导，我将阐明定义内分泌规范的调节机制， 通过测试RA信号和GATA之间的协同作用的假设，β细胞的发展和胰岛功能 转录因子对于胚胎胰腺发育和成人胰岛功能至关重要。